EP0942751B1 - Composition pour le traitement des neuropathies peripheriques contenant des antidepresseurs et/ou des inhibiteurs de monoamins-oxidase et/ou de la vitamine b12 et/ou un precurseur ou inducteur d'un neurotransmetteur - Google Patents

Composition pour le traitement des neuropathies peripheriques contenant des antidepresseurs et/ou des inhibiteurs de monoamins-oxidase et/ou de la vitamine b12 et/ou un precurseur ou inducteur d'un neurotransmetteur Download PDF

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Publication number
EP0942751B1
EP0942751B1 EP97930634A EP97930634A EP0942751B1 EP 0942751 B1 EP0942751 B1 EP 0942751B1 EP 97930634 A EP97930634 A EP 97930634A EP 97930634 A EP97930634 A EP 97930634A EP 0942751 B1 EP0942751 B1 EP 0942751B1
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EP
European Patent Office
Prior art keywords
neuropathy
vitamin
neurotransmitter
treatment
diabetic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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EP97930634A
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German (de)
English (en)
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EP0942751A1 (fr
Inventor
Andrew Peter Worsley
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WWK Trust
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WWK Trust
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Priority claimed from GBGB9614121.3A external-priority patent/GB9614121D0/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies

Definitions

  • the present invention relates to the preparation of a medicament for the treatment of various forms of peripheral neuropathy, especially painful neuropathies and diabetic neuropathy, including diabetic amyotrophy, mononeuritis, mononeuritis multiplex, cranial nerve palsies and autonomic neuropathy.
  • Diabetes mellitus is a metabolic disorder resulting in hyperglycaemia (raised blood sugar), polyuria (increased output of urine) and glycosuria (appearance of sugars (e.g. glucose) in the urine). Diabetes has been recognised as a major disease for centuries. In addition to defective carbohydrate metabolism, it can also lead to altered metabolism of lipids and proteins and patients are at risk of complications from microvascular and macrovascular diseases which are serious and may be fatal.
  • Insulin dependent diabetes results from failure of the islets of Langerhans ( ⁇ ) cells of the pancreas to produce sufficient insulin. This often arises as a result of auto-immunity directed against islet tissue.
  • Non-insulin-dependent diabetes may in part arise from altered efficiency of insulin receptor signalling (insulin resistance) or from a relative deficiency of insulin.
  • Detectable diabetic neuropathy occurs in approximately 60% of diabetic patients. Some 20% of diabetic patients show moderate to severe symptoms, the severity is generally thought to be linked to the duration of diabetic symptoms and the level of control using e.g. insulin, or oral hypoglycaemic agents such as the sulphonylureas.
  • Diabetic neuropathy may be mild, for example taking the form of "burning" or tingling in the feet or numbness and/or loss of vibration sense in the extremities, especially the feet. Moderate to severe symptoms of neuropathy include pain and spasm in the extremities (painful neuropathy with spasm). Diabetic amyotrophy is indicated by pain over the thigh and loss of quadriceps power, sometimes also loss of power in the lower leg resulting in foot drop. Autonomic neuropathy principally affects the nerves supplying the heart and viscera. Mononeuritis is usually caused by a single peripheral nerve palsy.
  • peripheral neuropathies include the following:
  • Type I diabetes insulin dependent diabetes
  • type II diabetes non-insulin dependent diabetes
  • neuropathy Both type I (insulin dependent) diabetes and type II (non-insulin dependent) diabetes are associated with neuropathy.
  • Type I diabetes commonly presents in relatively young adults, often with diabetic ketoacidosis, type II diabetes (also know as maturity onset diabetes) often occurs in middle age or in elderly patients.
  • Type II diabetes is particularly associated with the relatively late and severe onset of neuropathy.
  • gamolenic acid may reduce symptoms, and prevent the progression of abnormalities in nerve conduction studies in diabetic neuropathy.
  • WO 96/11009 discloses treatment of multiple sclerosis by some of the combinations of components employed in the present invention.
  • Vitamin B 12 has been proposed for the treatment of B 12 -deficiency associated neuropathy.
  • the present inventor has surprisingly found that a combination of an antidepressant or a monamine oxidase inhibitor (MAOI) with an inducer or a precursor of a neurotransmitter can be effective in the treatment of peripheral neuropathies, and in particular painful neuropathy.
  • the components of this medicament may be presented as a combined preparation for simultaneous, separate or sequential use in the treatment of various peripheral neuropathies. It has also been observed that a parallel or simultaneous administration of vitamin B 12 treatment, for example orally or by injection, may enhance the therapeutic effect of this combination.
  • the invention provides a method of making a medicament for the treatment of a patient suffering from a peripheral neuropathy, comprising admixing any one of the following combinations of components:
  • the invention provides a pharmaceutical composition containing as the only pharmaceutically active components vitamin B 12 and a precursor or inducer of a neurotransmitter.
  • Treatment may be simultaneous or separate including sequential administration of the components.
  • At least one pharmaceutically acceptable component or vehicle such as an incipient, carrier, buffer, stabiliser or other material, as discussed below.
  • kits or pack containing components A and B, or A and C, or A and B and C, or B and C, wherein component A the components being formulated for simultaneous, separate or sequential delivery in the treatment of peripheral neuropathy.
  • Particularly components A and C may be combined, and component B separate.
  • the diabetic neuropathy with which the present invention is concerned may be characterised by degeneration of the long nerves (the nerves of the peripheral nervous system) as a result of the metabolic disturbances of diabetes.
  • This can be contrasted with other neurodegenerative disorders such multiple sclerosis, the effects of which are concentrated in the central nervous system.
  • multiple sclerosis leads to demyelination of the neurons of the central nervous system (that is, degeneration of the myelin sheath which surrounds the neurons)
  • the toxic effects of diabetes occur in the body of the peripheral neuron, possibly due to the toxic effect of metabolites arising through the underlying diabetic disturbance of carbohydrate metabolism, or as a secondary effect of diabetic microvascular degeneration.
  • the result of the degenerative changes in the body of the peripheral neuron is reduced signal conductivity along the length of the nerve. It is believed that the initial generation of a signal and the passage of a signal across synapses may not be directly effected by the condition.
  • the present invention is applicable to any and all of peripheral neuropathies, particularly painful neuropathies, including those listed above in the introduction.
  • Preferred antidepressants for use in the present invention include tricyclic and tetracyclic antidepressants such as lofepramine and selected seritonin re-uptake inhibitors (SSRI). Lofepramine and certain other tricyclic antidepressants also show some monoamine oxidase inhibitor (MAOI) activity.
  • SSRI selected seritonin re-uptake inhibitors
  • MAOI monoamine oxidase inhibitor
  • Suitable antidepressants and MAOIs include mianserin, trimipramine, imipramine, clomipramine, amitriptyline, protriptyline, nortriptyline, fluvoxamine, fluoxetine, maprotiline, sertaline, venlaflaxine, pargyline, triazolopyridine, phenelzine, tranylcypromine, desipramine, moclopemide, dothiepin, doxepin, paroxetine, oxazine or viloxazine, amongst others.
  • a neurotransmitter inducer is a component which enhances or triggers production of a neurotransmitter.
  • a preferred neurotransmitter precursor for use in the present invention is L-phenylalanine (LPA).
  • LPA L-phenylalanine
  • L-tryptophan may also find use in the present invention.
  • amino acids such as L-tyrosine or other compounds such as tyramine may also find use in the present invention as a neurotransmitter, inducer or precursor.
  • Compounds may be provided as a metabolite of a precursor.
  • L-phenylalanine may be provided as a metabolite of aspartame.
  • the combination for treatment includes vitamin B 12 , this may be in the form of cyanocobalamin or hydroxycobalamin, to be administered orally or intramuscularly.
  • compositions provided herein may comprise an antidepressant or a monoamine oxidase inhibitor (MAOI) and a neurotransmitter precursor or inducer, or any other combination of components disclosed herein, as combined (simultaneous or sequential) actives.
  • MAOI monoamine oxidase inhibitor
  • compounds may be employed which mimic a given active in improving diagnostic status and/or ameliorating one or more symptoms of diabetic neuropathy (mimetics). Such compounds and their use are within the scope of the present invention.
  • derivatives or analogues of the antidepressant or MAOI which retain the antidepressant or MAOI activity, respectively.
  • compositions provided may be administered to individuals. Administration is preferably in a "therapeutically effective amount", this being sufficient to show benefit to a patient. Such benefit may be at least amelioration of at least one symptom.
  • the actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, eg decisions on dosage etc, is within the responsibility of general practitioners and other medical doctors. Dose regimens for the MAOIs and antidepressants may be within the range used for the treatment of depression (for which the standard starting dose of lofepramine is 140mg per day).
  • a possible range for administration of antidepressants is 10-210mg per day, although 50-70mg per day may be suitable.
  • a range of 100mg to 5g per day, preferably 500-2000mg/d (mg per day) may be employed, the dose increasing in proportion to the level of antidepressant or MAOI employed.
  • a 70mg dose of lofepramine may be combined with 500mg of L-phenylalanine given in the morning, this being supplemented with a further 500mg of L-phenylalanine given in the afternoon.
  • vitamin B 12 is co-administered
  • the amounts may be those generally recommended for daily intake of the vitamin or may be greater than that recommended as average daily intake.
  • the preferred average dosage range for vitamin B 12 in the invention is from 1mg every 3 months up to 1mg every 3 days. When symptoms are severe, this may be 1mg intramuscular hydroxycobalamin per week in an 8-10 week course at the start of treatment, perhaps reduced to 1mg every 10 days as treatment progresses.
  • the desired dosage level of vitamin B 12 may conveniently be given by weekly intramuscular injection, but doses ranging from 5 ⁇ g to 10mg may be given daily orally.
  • compositions according to the present invention may comprise, in addition to active ingredient, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • a pharmaceutically acceptable excipient such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material will depend on the route of administration, which may be oral, or by injection, e.g. cutaneous, subcutaneous or intravenous.
  • compositions for oral administration may be in tablet, capsule, powder or liquid form.
  • a tablet may comprise a solid carrier such as gelatin or an adjuvant.
  • Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
  • Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
  • L-tryptophan and L-phenylalanine are available in 500mg tablets.
  • a combined oral preparation in single tablet form containing all these components A, B and C, or for example components B and C, is feasible.
  • a treatment pack may contain the components separately.
  • amyotrophy Benefit in amyotrophy was noted within 3 hours of commencement of treatment. The subsequent addition of lofepramine 70 mg twice daily produced a further improvement. Within 3 weeks his diabetic amyotrophy was considerably improved.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Medicinal Preparation (AREA)
  • Steroid Compounds (AREA)

Claims (10)

  1. Méthode de fabrication d'un médicament pour le traitement d'un patient souffrant d'une neuropathie périphérique, comprenant le mélange de l'une des combinaisons suivantes de composants :
    A et B,
    A et C,
    B et C,
    A, B et C,
       où
    A est un antidépresseur ou un inhibiteur de la monoamine oxydase,
    B est la vitamine B12, et
    C est un précurseur ou inducteur d'un neurotransmetteur,
    avec au moins un composant pharmaceutiquement acceptable ou véhicule pour préparer un médicament approprié pour une administration à un patient.
  2. Méthode selon la revendication 1, où ledit médicament contient l'une des combinaisons suivantes de composants :
    A, B et C
    A et B,
    B et C,
    A et C,
    sous une forme ou de formes appropriées pour administration simultanée ou séparée.
  3. Méthode selon la revendication 1 ou 2, où la neuropathie est une neuropathie douloureuse.
  4. Méthode selon la revendication 1, 2 ou 3, où la neuropathie est une neuropathie diabétique.
  5. Méthode selon l'une quelconque des revendications 1 à 4, où A est un antidépresseur tricyclique ou tétracyclique ou un inhibiteur de la réabsorption de la séritonine sélectionné.
  6. Méthode selon la revendication 5 où A est lofépramine.
  7. Méthode selon l'une quelconque des revendications 1 ou 6, où B est sous la forme de cyanocobalamine ou hydroxycobalamine.
  8. Méthode selon l'une quelconque des revendications 1 à 7, où C et L-phénylalanine, L-tyrosine, L-tryptophane ou tyramine.
  9. Composition pharmaceutique contenant comme seuls composants pharmaceutiquement actifs de la vitamine B12 et précurseur ou inducteur d'un neurotransmetteur.
  10. Composition pharmaceutique selon la revendication 9, où le précurseur ou inducteur d'un neurotransmetteur est L-phénylalanine, L-tyrosine, L-tryptophane ou tyramine.
EP97930634A 1996-07-05 1997-07-04 Composition pour le traitement des neuropathies peripheriques contenant des antidepresseurs et/ou des inhibiteurs de monoamins-oxidase et/ou de la vitamine b12 et/ou un precurseur ou inducteur d'un neurotransmetteur Expired - Lifetime EP0942751B1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB9614121 1996-07-05
GBGB9614121.3A GB9614121D0 (en) 1996-07-05 1996-07-05 Combined medicament
GB9616019 1996-07-31
GBGB9616019.7A GB9616019D0 (en) 1996-07-05 1996-07-31 Combined medicaments
PCT/GB1997/001822 WO1998001157A1 (fr) 1996-07-05 1997-07-04 Composition pour le traitement des neuropathies peripheriques contenant des antidepresseurs et/ou des inhibiteurs de monoamins-oxidase et/ou de la vitamine b12 et/ou un precurseur ou inducteur d'un neurotransmetteur

Publications (2)

Publication Number Publication Date
EP0942751A1 EP0942751A1 (fr) 1999-09-22
EP0942751B1 true EP0942751B1 (fr) 2002-09-25

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EP97930634A Expired - Lifetime EP0942751B1 (fr) 1996-07-05 1997-07-04 Composition pour le traitement des neuropathies peripheriques contenant des antidepresseurs et/ou des inhibiteurs de monoamins-oxidase et/ou de la vitamine b12 et/ou un precurseur ou inducteur d'un neurotransmetteur

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US (1) US6335323B2 (fr)
EP (1) EP0942751B1 (fr)
AT (1) ATE224733T1 (fr)
AU (1) AU3451797A (fr)
CA (1) CA2259010A1 (fr)
DE (1) DE69715899T2 (fr)
DK (1) DK0942751T3 (fr)
ES (1) ES2184111T3 (fr)
PT (1) PT942751E (fr)
WO (1) WO1998001157A1 (fr)

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CA2259010A1 (fr) 1998-01-15
DE69715899T2 (de) 2003-05-28
EP0942751A1 (fr) 1999-09-22
US6335323B2 (en) 2002-01-01
ATE224733T1 (de) 2002-10-15
ES2184111T3 (es) 2003-04-01
AU3451797A (en) 1998-02-02
US20010008884A1 (en) 2001-07-19
DK0942751T3 (da) 2002-12-02
DE69715899D1 (de) 2002-10-31
PT942751E (pt) 2003-02-28
WO1998001157A1 (fr) 1998-01-15

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